Susceptibility to multiple sclerosis (MS) has been linked to certain HLA class II genes, although analysis of their exact function remains complicated. We have recently generated humanized class II transgenic mice (AEo) in the context of the new complete class II knockout MHCII-/- mice (produced by Benoist and Mathis) lacking all endogenous class II genes. In contrast to our "Abo" transgenic mice, in this new transgenic line "AEo", T cells express class II on their cell surface and can also present antigen. PLP91-110 peptide induced a severe EAE in HLA-DR3.AEo mice characterized by early disease onset and increased disease incidence as compared to DR3.Abo mice. Further mice with EAE showed severe inflammation and demyelination in CMS. Thus our new transgenic line simulates human MS both in form of expression of MHC class II on T cells as well as severe CNS demyelination. We hypothesize that in autoimmune diseases such as MS, auto- reactive CD4+ T cells expressing class II can present additional myelin antigen inside CNS thus propagate the inflammatory response which ultimately leads to CNS injury. Using this disease model, we will first explore role of human class II in the disease process with particular emphasis on neurological deficits and CNS histopathology. In CNS pathology, we will assess extent of demyelination, remyelination and axonal loss in spinal cord as well as the extent of inflammation, neuronal necrosis and white matter demyelination in brain. Next, we will analyze the expression of class II in different regions of brain and spinal cord as well as on CNS infiltrating cells and its role in modulating disease pathogenesis. We will also analyze role of CD4 T cells and CDS T cells both in pathogenesis as well as regulation of EAE as it has been suggested that they can play both pathogenic and protective role in MS/EAE. Next we will also analyze role and contribution of accessory molecules, costimulatory molecules, and cytokines in modulating the disease. Finally using double transgenic mice, we will study that how gene complementation between DR and DQ gene affect the disease initiation and progression in a susceptible HLA class II transgenic mice. The comprehensive studies outlined in this proposal should yield an insight into the role of HLA class II genes in predisposition, onset, progression, severity, modulation, and intervention of human multiple sclerosis. Finally, this new humanized class II model of EAE may provide new insight into the pathogenesis of MS.